Project Summary The bacterial microbiome of the mammalian gut has an indispensable role in a number of processes important to host survival, including fermentation, intestinal development, immune instruction and, through soluble mediators, the development of other organ systems. Dysbiosis has been linked to a number of pathologies, including metabolic syndrome and non-alcoholic fatty liver disease (NAFLD). Much less is known about the influence of the viral population of the mammalian gut, and no existing links between the enteric virome and host metabolic function have been shown. Norovirus is small +RNA virus that can establish persistent enteric infections in mice and humans and serves as a model of virus-host interactions at the intestinal mucosa. Previous experiments from our lab established that Murine Norovirus (MNV) infection can recapitulate some of the key functions of the commensal flora in microbiota-depleted mice. Remarkably, these effects were spread throughout the intestine and were not limited to the MNV replication niche in the ileum. Because MNV is able to influence intestinal physiology indirectly, we hypothesized that its presence can also have an effect on other organs such as the liver, in a manner similar to gut bacteria. We found that MNV-infected mice have an altered metabolic profile and a distinct transcriptional signature in the liver, both of which pointed to an increase in oxidative stress and inflammatory signaling. These changes resulted in an exacerbation of a dietary model of NAFLD. This provides the first evidence that localized enteric viral infection can significantly alter the outcome of a clinically relevant liver disease model. The goal of this proposal is to gain mechanistic insight into how this occurs. In this fellowship proposal, I aim to 1) determine the role of increased reactive oxygen species in MNV- mediated metabolic changes, 2) identify the immune signaling pathways responsible for MNV effects on the liver, and 3) determine which viral factors are required for the metabolic phenotype. Establishing the role of the gut virome in mammalian biology is important to our understanding of the microbiome. Moreover, noroviral infection is widespread in the human population and this research will highlight its relevance as a risk factor in metabolic diseases.